Prevent blinding retinal diseases by developing effective new treatments including gene and cell therapies.

Having demonstrated proof of principle for gene therapy in the first clinical trial of inherited blindness (Leber congenital amaurosis (LCA)2; RPE65 deficiency), and in several experimental models of other inherited and acquired disorders, I am working to develop a pipeline of new gene and cell therapies for the benefit of patients. Over the next 5 years, in close partnership with Professor Robin Ali, I intend to build a programme of early phase clinical trials for several blinding conditions, focussing in the first instance on those for which we have the best proof-of-concept studies. The aim is to expand the programme to include up to 5 clinical trials for additional disorders namely juvenile macular degeneration (Stargardt disease), childhood blindness (LCA4/AIPL1 deficiency), X-linked retinitis pigmentosa (RPGR deficiency), achromatopsia (CNGB3 deficiency) and neovascular age-related macular degeneration. This programme of experimental medicine will require substantial funding that is being secured from a wide range of sources, including government funding bodies, charities and industry. I have already attracted substantial funding to support the essential infrastructure and to maintain the unique expertise required to achieve the ambition. I have secured funding from the NIHR CLRN for a Gene Therapy Clinical Trials Administrator (60% FTE, 3 yrs), from the NIHR BRC an Experimental Medicine Regulatory Manager (50% FTE, 5 yrs) and from the Newman Trust for a Technical Assistant. Prof Ali and I have recently secured £750K from RP Fighting Blindness to maintain core personnel, whose expertise is essential for pre-clinical toxicology studies and the development of clinical trial protocols. Gene Therapy is one of the key Research Themes of the NIHR Biomedical Centre for Ophthalmology that has very recently succeeded in its application for a further 5 years of substantial funding. I have obtained sufficient funds to establish a Gene and Cell Therapy clinic within the NIHR BRC’s new Research and Treatment Centre, equipped with state-of-the-art technology and supported by dedicated clinical and administrative staff. This clinic will facilitate efficient recruitment of subjects for clinical trials. Data acquired on disease phenotype and progression will be critical for the development of clinical trials protocols to enable the reliable assessment of new interventions in ways that are timely and cost effective through the identification and validation of new visual and surrogate outcome measures. In collaboration with Prof Gary Rubin and Dr Marco Nardini we are developing pioneering tests of infant vision designed to assess reliably the impact of intervention on outcome. With all this support secured, we are in a very strong position to maintain our current clinical studies, complete preclinical development of gene therapy for the next target condition and secure substantial funding from other sources for specific projects to generate a broad programme of experimental medicine. Having secured substantial funding for the essential infrastructure and expertise for these trials we have also obtained funding from the Wellcome Trust for manufacture and preclinical testing of clinical grade vector. We now have everything in place for a phase I/II clinical trial of gene therapy for LCA4 except for the patient-associated costs. In this application I am requesting resource for NHS support costs and patients’ expenses that will enable us to proceed with the first trial of gene therapy for a photoreceptor disease. The proposal offers particularly good value for money because the manufacture and testing of clinical grade vector is already funded (Wellcome Trust and BRPS). The appointment of a postdoctoral research fellow as part of the award will provide essential expertise to help design and support this trial specifically and to expand our translational research capability in general. Pipeline of novel gene and cell therapies: We have established a pipeline of novel gene and cell therapies at every stage of development from proof of principle in experimental models, through preclinical development to clinical trials. The progress of development for each therapy is summarized below. 2) Phase I clinical trial of stem cell therapy for juvenile macular degeneration I am Chief Investigator for a phase I clinical trial of human embryonic stem cell-derived retinal pigment epithelial cells in juvenile macular degeneration (Stargardt disease). This condition is the commonest form of inherited blindness and is currently wholly untreatable. The trial will be the first in Europe of human embryonic stem cell therapy in any condition, and only the second outside the US. Funded by an Industry partner, the trial has recently been given full GTAC approval and is currently under consideration by the MHRA. In addition, I am collaborating with Prof Robin Ali and Dr Rachel Pearson to develop the means to transplant photoreceptor cells, derived from precursor cells or from induced pluripotent stem (iPS) cells. The results of this work demonstrate proof of principle that transplanted photoreceptor cells can survive, integrate, form functioning synapses and mediate vision (Maclaren et al Nature 2006, Pearson et al Nature in revision). We anticipate performing an early phase clinical trial of photoreceptor transplantation within 5 to 10 years. 3) Phase I/II clinical trial of gene therapy for LCA4 (AIPL1 deficiency) Our ongoing clinical trial of gene therapy addresses LCA2 (RPE deficiency) in which the gene defect affects retinal pigment epithelial cells. In our second trial of gene therapy trial we propose to target a form of the condition in which the gene defect is specific to photoreceptor cells. We believe that LCA4 (AIPL1 deficiency) is a very good target for a first clinical trial of gene therapy for a photoreceptor defect because the rapid progression in this condition will enable rapid assessment of the impact of intervention (Tan et al Hum Mol Genet 2009). The results of our preclinical studies demonstrate the most effective rescue of a severe photoreceptor defect reported to date and suggest that AIPL1 defects in humans will indeed be particularly amenable to gene therapy.(Tan et al Hum Mol Genet 2009). Together with our gene therapy colleagues at UCL, we have secured funding from the Wellcome Trust to develop a facility for manufacture of AAV and lentivirus-based gene therapy vectors. This facility was recently accredited by MHRA for manufacture clinical grade gene therapy vectors for use in LCA trials, and we are currently manufacturing clinical grade gene therapy vector for use in a clinical trial for LCA4. We have recently secured the financial support for the preclinical studies of GMP-grade vector toxicity and efficacy from RP Fighting Blindness. Having already established the infrastructure and secured the resources to manufacture vector, in this application I am requesting only the clinical costs of the phase I/II clinical trial of gene therapy for LCA4. This will be an open label dose-escalation trial of AAV2/8.hRKp.hAIPL1 delivered subretinally in up to 12 human subjects. The support requested will enable me to recruit subjects, perform subretinal vector administration and measure outcome. Proof of principle of gene therapy for this photoreceptor-specific form of LCA by first-in-man application of highly efficient AAV2/8 vectors in the eye will expand significantly the range of retinal disorders potentially amenable to gene therapy, paving the way for the treatment of other severe childhood and adult-onset retinal dystrophies caused by defects in photoreceptor-specific genes. 4) Phase I/II clinical trial of gene therapy for RP3 (RPGR-deficiency) Since X-linked RP3, which is caused by mutations in the RPGR gene, is both severe, and relatively common, the development of a successful gene therapy will have a major impact on the prevalence of blindness. We have been able to show that gene therapy improves outcome in a preclinical model of the condition (Pawlyk et al, in preparation). Although the rate of disease progression in RP3 is relatively slow, characteristic changes in fundus autofluorescence provide an invaluable surrogate outcome measure to assess the impact of intervention in clinical trials and we are currently developing a humanised AAV-RPGR vector suitable for use in a clinical trial. 5) Phase I/II clinical trial of gene therapy for achromatopsia (CNGB3 deficiency) Achromatopsia is defined by a lack of cone function but, in contrast to the disorders described above, is associated with little or no photoreceptor degeneration. In preclinical studies, administration of AAV2/8-CNGB3 leads to a complete rescue of the cone activity on electroretinography and restoration of visual acuity (Carvalho et al, Hum Mol Genet 2011). The survival of non-functional cone photoreceptor cells in this condition presents a wide window of opportunity for intervention in humans and the potential for improved cone function will enable rapid assessment of the impact of intervention in a clinical trial. To fund the pre-clinical developmental work on the achromatopsia (CNBG3) project, a grant application for a Wellcome Senior Investigator Award has been submitted. 6) Phase I/II clinical trial of gene therapy for neovascular AMD Currently available local therapies targeting vascular endothelial growth factor (VEGF) can improve outcome but are short-lived in the eye. Having previously demonstrated that gene therapy can improve outcome in experimental models of age-related macular degeneration and diabetic retinopathy, I have obtained funding from UCL’s Therapeutic Innovation Fund to developing a novel therapeutic antibody for sustained local delivery by vector-mediated expression in neovascular age-related macular degeneration and diabetes. I have isolated a polyclonal population of human domain antibody fragments that can target specifically VEGFA-165 and are performing lead screening, affinity maturation, expression and in vitro functional assays. By year 2 of the Professorship I expect to have identified and validated candidate antibody fragments for in vivo studies and further preclinical development, leading subsequently to a patent, clinical trials and commercial application. Having demonstrated proof of principle for gene therapy of retinal disease we have made significant progress in establishing a pipeline of new gene and cell therapies, at every stage of development for the benefit of patients. We have secured funding for infrastructural support, expertise, the production of clinical grade vector and preclinical testing of vector for a trial of gene therapy for the photoreceptor disease LCA4. Provision of NHS support costs is all that we require to proceed with this trial. Proof of principle in this trial will expand significantly the range of retinal disorders potentially amenable to gene therapy, paving the way for the treatment of other blinding disorders. The appointment of a postdoctoral research fellow as part of the award will provide essential expertise to help design and support the trial specifically and to expand our translational research capability in general. An NIHR Research Professorship will enable me to ensure that the huge potential of this programme of experimental medicine is fully realised by translation into better vision health for our populations. 1) Phase I/II trials of gene therapy for LCA2 (RPE65 deficiency) Having reported the first results of this study (Bainbridge et NEJM 2008) we are continuing the longer-term evaluation of outcome in all 12 children and adults recruited. We have developed an optimised version of the AAV-RPE65 construct and are planning a follow-up trial in which we will use this vector, which will be produced to GMP standard at the UCL Cancer Institute as part of the UCL gene therapy consortium. We have recently secured funding from the MRC’s Development Pathway Funding Scheme to finance the pre-clinical development of this vector for a clinical trial of this optimized vector.